This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it relates to certain non-peptide GnRH antagonists or agonists and to their preparation. These non-peptide GnRH agents have advantageous physical, chemical, and biological properties, and are useful medicaments for diseases or conditions mediated by modulation of the pituitary-gonadal axis. The invention also relates to methods for treating individuals needing therapeutic regulation of GnRHxe2x80x94i.e., methods for treating diseases and conditions mediated by GnRH regulationxe2x80x94involving the administration of such GnRH agents.
Gonadotropin-Releasing Hormone (GnRH), also known as luteinizing hormone-releasing hormone (LH-RH), plays a central role in the biology of reproduction. Various analogs have been used for an increasing number of clinical indications. The GnRH decapeptide (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 or p-EHWSYGLRPG-NH2) is produced in neurons of the medial basal hypothalamus from a larger precursor by enzymatic processing. The decapeptide is released in a pulsatile manner into the pituitary portal circulation system where GnRH interacts with high-affinity receptors (7-Transmembrane G-Protein Coupled Receptors) in the anterior pituitary gland located at the base of the brain. In the pituitary, GnRH triggers the release of two gonadotropic hormones (gonadotropins): luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In testes and ovaries, LH stimulates the production of testosterone and estradiol, respectively. FSH stimulates follicle growth in women and sperm formation in men. When correctly functioning, the pulse-timed release and concentration levels of GnRH are critical for the maintenance of gonadal steroidogenesis and for normal functions of reproduction related to growth and sexual development.
The pituitary response to GnRH varies greatly throughout life. GnRH and the, gonadotropins first appear in the fetus at about ten weeks of gestation. The sensitivity to GnRH declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnRH increases, and pulsatile LH secretion ensues. Later in puberty and throughout the reproductive years, pulsatile release of GnRH occurs throughout the day, with LH responsiveness being greater than that of FSH. Pulsatile GnRH release results in pulsatile LH and FSH release from the pituitary and, hence, testosterone and estradiol release from the gonads. After menopause, FSH and LH-concentrations rise, and post-menopausal FSH levels are higher than those of LH.
Chronic administration of GnRH agonists and antagonists to animals or to man results in decreased circulating levels of both LH and FSH. GnRH agonists are compounds that mimic endogenous GnRH to stimulate receptors on the pituitary gland, resulting in release of LH and FSH. After a transient rise in gonadal hormone production or xe2x80x9cflarexe2x80x9d response, chronic administration of GnRH agonists results in a down-regulation of GnRH receptors. GnRH receptor down-regulation and desensitization of the pituitary results in a decrease of circulating levels of LH and FSH. In spite of the symptom-exacerbating hormonal flare experienced, GnRH agonists have been the treatment of choice for sex-steroid-dependent pathophysiologies. For example GnRH agonists have been used to reduce testosterone production, thereby reducing prostate volume in benign prostatic hyperplasia (BPH) and slowing tumor growth in prostate cancer. These compounds have also been used to treat breast and ovarian cancers.
Recently, GnRH antagonists have become available for clinical evaluation GnRH antagonists have an immediate effect on the pituitary without the observed flare associated with agonists. Use of GnRH antagonists (e.g., decapeptides) has been reported in the literature for treatment of breast, ovarian, and prostatic cancers. Other uses of antagonists, like agonists, include endometriosis (including endometriosis with pain), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), prostatic hypertrophy, amenorrhea (e.g., secondary amenorrhea), uterine fibroids, and precocious puberty. These agents may also be useful in the symptomatic relief of premenstrual syndrome (PMS), pregnancy regulation, infertility remedy, or menstruation regulation. Furthermore, antagonists may be useful to regulate the secretion of gonadotropins in male mammals to arrest spermatogenesis (e.g., as male contraceptives), and for treatment of male sex offenders. Importantly, GnRH antagonists (and agonists) have found utility in treatments where a reversible suppression of the pituitary-gonadal axis is desired and in the treatment of sleep disorders (e.g., apnea.)
For over fifty years, androgen deprivation has been the most effective systematic therapy for the treatment of metastatic carcinoma of the prostate. The rationale is simplexe2x80x94the prostate gland requires androgens for proper growth, maintenance, and function. Yet, prostate cancer and benign prostate hyperplasia are common in men and develop in an environment of continuous androgen exposure. Thus, utilizing a GnRH antagonist to interrupt the pituitary-gonadal axis reduces androgen production and results in tumor growth modulation. Furthermore, GnRH antagonists may have a direct effect on tumor growth by blocking receptors on the tumor cells. For those cancer types that respond both to sex hormones and to GnRH directly, antagonists should be effective in slowing tumor growth by these two mechanisms. Since GnRH receptors are present on many prostate and breast cancer cells, it has recently been speculated that GnRH antagonists may also be effective in treating non-hormone-dependent tumors. Recent literature examples indicate that GnRH receptors are present on a number of cancer cell lines, including:
prostate cancer: GnRH agonists exert both in vitro, and in vivo, a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines [Montagnani et al., Arch. Ital. Urol. Androl., 69(4), 257-263 (1997); Jungwirth et al., xe2x80x9cGnRH Antagonist Inhibit the Growth of Androgen-Independent PC-3 Prostate Cancer in Nude Mice,xe2x80x9d Prostate, 32(3), 164-172 (1997)];
ovarian cancer: The demonstration of GnRH receptors in human ovarian cancers provides a rationale for the use of therapeutic approaches based on GnRH analogues in this malignancy [Srkalovic et al., Int. J. Oncol., 12(3), 489-498 (1998)].
breast cancer: Breast cancer is the most common type of cancer in women over the age of forty and is the leading cause of cancer-related death in women. Systematic endocrine intervention represents a major treatment option for the management of advanced breast cancer, especially with estrogen-dependent cancers. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer [Kottler et al., Int. J. Cancer, 71(4), 595-599 (1997)].
GnRH agents may also be useful in treating cancer through generation of thymus re-growth and therefore induction of the development of new T-cells. See Norwood Abbey press release dated Mar. 5, 2001, xe2x80x9cNorwood Abbey Announces Breakthrough In Immunology.xe2x80x9d These white blood cells, which develop in the thymus gland, are a fundamental component of the immune system""s involvement in a range of diseases, including viral infections, transplant organ rejection, cancer, and autoimmune diseases. Thus, for example, since the human immunodeficiency virus (HIV) preferentially infects and destroys T-cells, GnRH agents may be useful for treating HIV infection or acquired immune deficiency syndrome (AIDS). Additionally, GnRH agents may be useful in combating infection in tissue-transplant patients where immunosuppressive drugs, which remove T-cells, are being administered to counteract rejection of the transplanted tissue. Similarly, since adequate and effective T-cells help defend against cancer, and chemotherapy and radiation regimens detrimentally impact T-cells, GnRH agents may be useful in conjunction with a chemotherapeutic agent or radiation regimen in treating cancer. Furthermore, GnRH agents may be useful for treating autoimmune diseases such as multiple sclerosis (MS), where T-cells are produced that react against a molecule surrounding nerve cells. GnRH agents may also benefit patients who have been shown to have a decreased likelihood of immune recovery with HAART. See AIDS. 2001; 15:1576-1578.
Heretofore, available GnRH antagonists have included peptide analogs of GnRH. See, e.g., International Publication Nos. WO 93/03058, WO 99/50276, WO 00/12521, and WO 00/12522; Koppan et al., Prostate, 38(2), 151-158 (1999); and Nagy et al., Proc Natl Acad Sci USA, 97(2), 829-834 (2000). Though peptide antagonists of peptide hormones are often quite potent, the use of peptide antagonists is typically associated with problems because peptides are degraded by physiological enzymes and often poorly distributed within the organism being treated.
A non-peptide antagonist of the human leuteinizing hormone-releasing hormone (LHRH) receptor was reported by Cho et al. (J Med Chem, 41(22), 4190 (1998)). Other non-peptide GnRH antagonists have been reported in the literature. For example, certain quinolone-6-carboxamides were reported by Walsh et al. in Bioorg and Med Chem Ltrs., 10, 443-447 (2000). Certain tricyclic diazepines and cyclic pentapeptides were reported in International Publication Nos. WO 96/38438 and WO 96/34012, respectively. Certain tetrahydroisoquinoline derivatives were reported in U.S. Pat. No. 5,981,521. For additional examples of non-peptide GnRH antagonists, see International Publication Nos. WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 99/44987, WO 00/04013, WO 00/12522, WO 00/12521, WO 00/04013, WO 00/68959, and WO 01/29044. Additionally, active non-peptide GnRH agents are described in International Publication No. WO 00/20358.
Despite recent advances, there continues to be a need for potent non-peptide antagonists of the peptide hormone GnRH with desirable pharmacokinetic and pharmacological properties. For example, there is a desire for non-peptide GnRH agents having advantageous physical, chemical and biological properties, which are useful medicaments for treating diseases mediated via the pituitary-gonadal axis and by directly targeting the receptor on tumor cells. Furthermore, there is a need for non-peptide GnRH agents having a desirable combination of activity, solubility, and ADME (absorption, distribution, metabolism, excretion) properties. There is also a need for GnRH agents that act upon receptors to treat both hormone-dependent and hormone-independent cancers.
In one general aspect, the invention is directed to compounds represented by the following Formula I: 
wherein:
Y is O or (CH2)n where n is 1 or 2;
R1 and R2 are each independently: hydrogen; xe2x95x90O; or a halogen; or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94S(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituied aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
W is O or C(R3)(R4), where R3 and R4 are each independently selected from the group consisting of hydrogen; xe2x95x90O; and halogens; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)Rc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
R5 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R6 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
Z is O or NRx, where Rx is hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl; and
R7 is hydrogen; a halogen; or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90Oxe2x80x94S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94C(O)ORc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcR, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloaplkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substitute with an unsubstituted alkyl group;
or R7 and Rx cyclize to form a heterocycloalkyl or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of xe2x95x90O; and halogens; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens, xe2x80x94O; xe2x80x94S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x80x94NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
In preferred embodiments of compounds of the formula I:
Y is O;
W is C(R3)(R4), where R3 and R4 are each independently selected from the group consisting of hydrogen; and alkyl and heteroalkyl groups unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and
R1 and R2 are each independently hydrogen; or an alkyl or heteroalkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group, and where at least one of R1 or R2 is not hydrogen;
R5 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R6 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
Z is O or NRx, where Rx is hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl; and
R7 is an alkyl, alkenyl, heteroalkyl, or an alkynyl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)xe2x80x94H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups-unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc; xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two-or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
In other preferred embodiments:
Y is O;
W is C(R3)(R4), where R3 and R4 are each independently selected from the group consisting of hydrogen, unsubstituted alkyls, and unsubstituted heteroalkyls;
R1 and R2 are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl, and where at least one of R1 or R2 is not hydrogen;
R5 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R6 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
Z is NH or O, and
R7 is an alkyl, alkenyl, heteroalkyl, or an alkynyl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc , xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
In another general aspect, the invention is directed to compounds represented by the following Formula II: 
wherein:
T is O or (CH2)n, where n is 1 or 2;
V is O or C(R8)(R9), where R8 and R9 are each independently selected from the group consisting of hydrogen; xe2x95x90O; and halogens; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OHxe2x80x94, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S), xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(O(O2)NH2; xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRc, xe2x80x94NRcC(O)NRc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted, alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
R10 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R11 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R12 is hydrogen or a halogen, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORcc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and
U is O or NRx, where Rx is hydrogen, alkyl, or heteroalkyl;
or R12 and Rx cyclize to form a heterocycloalkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.
In preferred embodiments of formula II:
T is O;
V is C(R8)(R9), and R8 and R9 are each independently selected from the group consisting of hydrogen and alkyl, alkenyl, heteroalkyl, and alkynyl groups unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x80x94NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2)zxe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRcRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
R10 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
R11 is hydrogen, halogen, unsubstituted C1-C3 alkyl, or unsubstituted C1-C3 heteroalkyl;
U is NH or O; and
R12 is an alkyl, alkenyl, heteroalkyl, or alkynyl groups unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; xe2x95x90O; xe2x95x90S; xe2x80x94CN; and xe2x80x94NO2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, xe2x80x94(CH2)zCN where z is an integer from 0 to 4, xe2x95x90NH, xe2x80x94NHOH, xe2x80x94OH, xe2x80x94C(O)H, xe2x80x94OC(O)H, xe2x80x94C(O)OH, xe2x80x94OC(O)OH, xe2x80x94OC(O)OC(O)H, xe2x80x94OOH, xe2x80x94C(NH)NH2, xe2x80x94NHC(NH)NH2, xe2x80x94C(S)NH2, xe2x80x94NHC(S)NH2, xe2x80x94NHC(O)NH2, xe2x80x94S(O2)H, xe2x80x94S(O)H, xe2x80x94NH2, xe2x80x94C(O)NH2, xe2x80x94OC(O)NH2, xe2x80x94NHC(O)H, xe2x80x94NHC(O)OH, xe2x80x94C(O)NHC(O)H, xe2x80x94OS(O2)H, xe2x80x94OS(O)H, xe2x80x94OSH, xe2x80x94SC(O)H, xe2x80x94S(O)C(O)OH, xe2x80x94SO2C(O)OH, xe2x80x94NHSH, xe2x80x94NHS(O)H, xe2x80x94NHSO2H, xe2x80x94C(O)SH, xe2x80x94C(O)S(O)H, xe2x80x94C(O)S(O2)H, xe2x80x94C(S)H, xe2x80x94C(S)OH, xe2x80x94C(SO)OH, xe2x80x94C(SO2)OH, xe2x80x94NHC(S)H, xe2x80x94OC(S)H, xe2x80x94OC(S)OH, xe2x80x94OC(SO2)H, xe2x80x94S(O2)NH2, xe2x80x94S(O)NH2, xe2x80x94SNH2, xe2x80x94NHCS(O2)H, xe2x80x94NHC(SO)H, xe2x80x94NHC(S)H, and xe2x80x94SH groups unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, xe2x95x90O, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(CH2), xe2x80x94CN where z is an integer from 0 to 4, xe2x80x94ORc, xe2x80x94NRcORc, xe2x80x94NRcRc, xe2x80x94C(O)NRc, xe2x80x94C(O)ORc, xe2x80x94C(O)Rc, xe2x80x94NRcC(O)NRc, xe2x80x94NRcC(O)Rc, xe2x80x94OC(O)ORc, xe2x80x94OC(O)NRcRc, xe2x80x94SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
More preferably, the invention is directed to compounds described in the examples herein and to pharmaceutically acceptable salts of such compounds.
In addition to compounds of formulae I and II, the invention is also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. Such compounds, salts, prodrugs and metabolites are at times collectively referred to herein as xe2x80x9cGnRH agents.xe2x80x9d
The invention also relates to pharmaceutical compositions each comprising a therapeutically effective amount of a GnRH agent of the invention in combination with a pharmaceutically acceptable carrier or diluent.
Further, the invention is directed to therapeutic methods for treating a disease or condition mediated by regulating secretion of gonadotropins or suppressing the pituitary-gonadal axis in a mammal, comprising administering a therapeutically effective amount of a compound of formula I or II, or a salt, prodrug, or metabolite thereof. The invention is also directed to methods for antagonizing gonadotropin-releasing hormone in a patient subject suffering from a gonadotropin-releasing hormone derived disorder, comprising administering to the patient a therapeutically effective amount of a compound of formula I or II or a salt thereof. In one preferred embodiment, the method is for treating a disorder that is a sex hormone related condition, such as of endometriosis, polycystic ovarian disease, uterine fibroids, or precocious puberty. In another preferred embodiment, the method is for treating a sex hormone dependent cancer (such as prostatic cancer, uterine cancer, breast cancer, and pituitary gonadotrophe adenomas), benign prostatic hypertropy, amenorrhea syndrome, or myoma of the uterus. The invention is also directed to methods employing a compound of formula I or II, or a salt thereof, for treating premenstrual syndrome, regulating pregnancy, treating infertility, or regulating menstruation in a patient. Moreover, the invention is directed to methods for treating sleep apnea by administering a compound of formula I or II or a salt thereof.
Other aspects, features, and advantages of the invention will become apparent from the detailed description of the invention and its preferred embodiments.